SRNAS REMYELINATION

The role of small RNAs in remyelination

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 Obiettivo del progetto (Objective)

'In diseases of the central nervous system (CNS) such as Multiple Sclerosis (MS), myelinating cells are the principal affected cells. Following pathological loss of myelin, remyelination by oligodendrocyte precursors (OPC) occurs but becomes increasingly incomplete and eventually fails in the majority of lesions. Understanding the molecular basis of myelination and remyelination and the regulation of the cells that achieve myelination and remyelination is primordial for both fundamental and clinical research.

The host lab and others have shown, mainly using conditional transgenic approaches in mice, that Dicer, an enzyme responsible for the maturation of small RNAs, including miRNAs, is essential for correct development of myelinating cells and their interactions with neurons. However, the functional role of small RNAs in adult remyelination has not been explored. Thus, the ETH Fellow will examine the importance of Dicer and DGCR8 (the latter is required specifically for miRNA maturation) during remyelination after injury. To achieve this goal, we will use conditional floxed alleles in the mouse that target these two genes. In combination with a well characterized tamoxifen-inducible PDGFRα-CreERT2 allele, we will eliminate DGCR8 and Dicer specifically in adult oligodendrocytes precursors cells followed by spinal cord injection of lysolecithin, a well-controlled demyelination/remyelination model. In parallel and in collaboration with other lab members, the ETH fellow will perform complementary neuroprotection experiments using a suitable neuron-specific inducible Cre recombinase line combined with the Dicer or the DGCR8 conditional lines. The work is embedded firmly in ongoing work in the host lab examining the functional role of Dicer and DGCR8 in glial development.'

Introduzione (Teaser)

Delineation of the molecular mechanisms implicated in the process of myelination could help design novel targeted therapies for neurodegenerative disorders.

Descrizione progetto (Article)

Many diseases of the central nervous system, such as multiple sclerosis (MS), are associated with a loss of the insulating myelin sheath around neuronal axons. This demyelination impairs transmission of nerve impulses and thus the body cannot properly communicate signals.

At the initial stages of MS, an attempt to remyelinate axons is observed but this process fails, and axons ultimately become damaged. In an experimental setting, the process of remyelination is linked with activation and differentiation of oligodendrocyte precursors (OPCs). During OPC differentiation certain genes are switched on through the concerted action of transcriptional activators, repressors and miRNAs.

The EU-funded project 'The role of small RNAs in remyelination' (SRNAS REMYELINATION) concentrated on the regulatory role of miRNA and other epigenetic regulators in neurodegeneration and neuroprotection. In this context, scientists used transgenic animals with a deletion in Dicer or Pasha, key molecules responsible for the maturation of small RNAs (sRNAs).

It is possible to induce and carefully control the demyelination process in these animals by injecting the substance lysolecithin. Following experimentally induced demyelination, researchers observed that the protein Pasha, which is required for correct miRNA processing, was instrumental in maintaining a functional neuronal network. Mice lacking the Pasha-encoding gene DGCR8 induced a Parkinsonism-like neuropathology associated with abnormal myelin deposits and axonal degeneration in the white matter of the spinal cord.

These findings prompted scientists to steer their work towards the identification of the miRNA molecules responsible for this phenotype. Coupled with investigation of the affected signalling pathways, the SRNAS REMYELINATION study aims to provide important insight into demyelination and identify neuroprotective molecules.